The long-term goal of the proposed four-year Career Development Award is to allow Candidate to develop an independent research career in translational studies linking basic aspects of critical illness pathophysiology to clinical outcomes. The candidate is interested in understanding the mechanisms of microcirculatory endothelial dysfunction and repair in patients who sustain trauma, sepsis or any other acute injury. As a part of this Award, she will develop an expertise in sidestream dark-field (SDF) video microscopy, a non-invasive technique that directly visualizes microcirculatory vessels and perfusion in human subjects. Her mentoring team features a number of renowned experts in research of sepsis and endothelial dysfunction. Her primary mentor, Dr. Lyle Moldawer, is an outstanding investigator and accomplished mentor. The candidate's research plan builds upon her mentors own NIH-funded research examining interactions between the early innate immune response and adaptive immune dysfunction in sepsis. In addition, the current research proposal expands upon the Candidate's previous research experience in studying endothelial progenitor cells (EPCs) in chronic kidney disease with her co-mentor, Dr. Mark S. Segal. Her clinical appointment in a multidisciplinary surgical intensive care unit will provide the ideal setting in which to conduct interdisciplinary translational research. The proposed career development plan incorporates a multi-disciplinary program designed to provide a closely mentored, patient-oriented clinical and translational research experience in association with a comprehensively structured didactic curriculum in clinical investigation, statistics and epidemiology through enrollment in the Advanced Postgraduate Program in Clinical Investigation. The goals of the research proposal are to characterize the effect of EPCs on microcirculatory dysfunction in the first 48 hours onset of severe sepsis (SS) and to determine the potential role of EPCs as markers of endothelial repair. The hypothesis is that tissue hypoxia in sepsis, through downregulation of angiogenic factors, provides a stimulus for the mobilization of EPCs from the bone marrow into the circulation, and that mobilization of EPCs is associated with endothelial repair and restoration of microcirculatory perfusion. These hypotheses will be tested in a single-center, prospective, observational cohort study of patients with SS in order to measure mobilization and functional properties of EPCs in the first 48 hours onset of SS and to determine their effect on the recovery of microcirculatory dysfunction (Specific Aim 1), to correlate mobilization of EPCs to the plasma levels of hypoxia-induced angiogenic factors (Specific Aim 2) and to determine the effect of microcirculatory dysfunction on organ recovery and hospital survival (Specific Aim 3). This Award will foster a career focused on understanding the mechanisms of microcirculatory endothelial dysfunction and repair in critical illness in order to develop the methodology for use of progenitor cells as biological markers for disease monitoring in critically ill patients. PUBLIC HEALTH RELEVANCE: Severe sepsis is a leading cause of mortality in the intensive care unit and imposes a large burden on healthcare systems worldwide. Our research approach may provide new monitoring tools for endothelial dysfunction and repair in patients with severe sepsis, eventually leading to improved care and outcomes for patients with severe sepsis.